In most tissues, cells are surrounded by an extracellular matrix (ECM) containing proteins such as collagen, laminin, and fibronectin. As mammals age and in some disease states, the extracellular matrix in certain areas of the body (e.g., in synovial joints, the vitreous humor, the spinal discs, the skin, etc.) can degrade, causing undesirable symptoms, such as various forms of arthritis, loss of vision, and the like.
Lubricin, also known as superficial zone protein (SZP) or PRG4, is a mucinous glycoprotein secreted by tissues lining the interior surfaces of animal joints (see Schumacher, B. L., et al., Arch Biochem Biophys, 1994, 311(1): 144-52). Lubricin acts as a chondroprotective barrier against direct solid-to solid contact in joints when the kinematic conditions are conducive to surface sliding in the boundary lubrication regime, characterized by the formation of an adsorbed molecular layer conformal with the articular tissue surface topography (see Neu, C. P., K. Komvopoulos, and A. H. Reddi, Tissue Engineering, Part B: Reviews, 2008). In the absence of a strongly adsorbing, continuous, self-replenishing boundary lubricant layer, intermittent asperity-asperity interactions lead to rapid deterioration of the join surface by various mechanical wear processes, such as adhesion, abrasion, surface fatigue, and delamination. Lubricin tribosupplementation has been shown to reduce cartilage degeneration (see Jay, G. D., et al., Arthritis and rheumatism, 2012, 64(4): 1162-71, and Teeple, E., et al., The American Journal of Sports Medicine, 2011, 39(1): 164-72). Reducing friction at the articular cartilage interface will suppress cartilage wear and surface damage.
Another extracellular matrix is the vitreous humor, a complex gel-like network which fills the posterior cavity of the eye, is composed of approximately 99 wt % water, 0.9 wt % salts, less than 0.1 wt % heterotypic collagen fibrils (type II, V/XI and IX), and a hyaluronan network. It serves several purposes (including developmental, optical, protective) and its degradation has been implicated in several ocular pathologies, such as retinal tear, retinal detachment, retinal edema, choroidal detachment, vitreous hemorrhage, and glaucoma.
In addition, degeneration of the nucleus pulposus, a gel-like substance is the inner core of the spinal disc, results in reduced ability of the spinal disc to transmit loads evenly and efficiently between vertebral bodies, and leads to damage in the annular region of the disc, known as the annulus fibrosis. The nucleus pulposus functions to distribute hydraulic pressure in all directions within each disc under compressive loads and is comprised of chondrocyte-like cells, collagen fibrils, and proteoglycan aggrecans that aggregate through hyaluronic chains. Fissures or tears in the annulus can translate into a disc that herniates or ruptures, resulting in impingement of the nerves in the region of the disc and finally lower back or leg pain.
This disclosure provides extracellular matrix-binding synthetic peptidoglycans for use in supplementing and/or replacing extracellular matrix fluids in the body, thus treating and/or preventing diseases or disorders resulting from the degradation thereof.